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rdf:type |
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lifeskim:mentions |
umls-concept:C0017262,
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0165519,
umls-concept:C0185117,
umls-concept:C0301630,
umls-concept:C0439852,
umls-concept:C0678226,
umls-concept:C1257757,
umls-concept:C2911684,
umls-concept:C2916813
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pubmed:issue |
36
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pubmed:dateCreated |
2002-9-2
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pubmed:abstractText |
Rat renal mesangial cells express high levels of matrix metalloproteinase 9 (MMP-9) in response to inflammatory cytokines such as interleukin 1beta (IL-1beta). We tested whether ligands of the peroxisome proliferator-activated receptor (PPARalpha) could influence the cytokine-induced expression of MMP-9. Different PPARalpha agonists dose-dependently inhibited the IL-1beta-triggered increase in gelatinolytic activity mainly by decreasing the MMP-9 steady-state mRNA levels. PPARalpha agonists on their own had no effects on MMP-9 mRNA levels and gelatinolytic activity. Surprisingly, the reduction of MMP-9 mRNA levels by PPARalpha activators contrasted with an amplification of cytokine-mediated MMP-9 gene promoter activity and mRNA expression. The potentiation of MMP-9 promoter activity functionally depends on an upstream peroxisome proliferator-responsive element-like binding site, which displayed an increased DNA binding of a PPARalpha immunopositive complex. In contrast, the IL-1beta-induced DNA-binding of nuclear factor kappaB was significantly impaired by PPARalpha agonists. Most interestingly, in the presence of an inducible nitric-oxide synthase (iNOS) inhibitor, the PPARalpha-mediated suppression switched to a strong amplification of IL-1beta-triggered MMP-9 mRNA expression. Concomitantly, activators of PPARalpha potentiated the cytokine-induced iNOS expression. Using actinomycin D, we found that NO, but not PPARalpha activators, strongly reduced the stability of MMP-9 mRNA. In contrast, the stability of MMP-9 protein was not affected by PPARalpha activators. In summary, our data suggest that the inhibitory effects of PPARalpha agonists on cytokine-induced MMP-9 expression are indirect and primarily due to a superinduction of iNOS with high levels of NO reducing the half-life of MMP-9 mRNA.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/Dactinomycin,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 9,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide,
http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Peroxisome Proliferators,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Synthesis Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Tissue Inhibitor of...,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/omega-N-Methylarginine,
http://linkedlifedata.com/resource/pubmed/chemical/pirinixic acid
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
6
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pubmed:volume |
277
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
33518-28
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:12093797-Animals,
pubmed-meshheading:12093797-Base Sequence,
pubmed-meshheading:12093797-Binding Sites,
pubmed-meshheading:12093797-Cells, Cultured,
pubmed-meshheading:12093797-Cloning, Molecular,
pubmed-meshheading:12093797-Cytokines,
pubmed-meshheading:12093797-DNA,
pubmed-meshheading:12093797-Dactinomycin,
pubmed-meshheading:12093797-Dose-Response Relationship, Drug,
pubmed-meshheading:12093797-Enzyme Inhibitors,
pubmed-meshheading:12093797-Humans,
pubmed-meshheading:12093797-Interleukin-1,
pubmed-meshheading:12093797-Matrix Metalloproteinase 9,
pubmed-meshheading:12093797-Molecular Sequence Data,
pubmed-meshheading:12093797-Nitric Oxide,
pubmed-meshheading:12093797-Oligonucleotides,
pubmed-meshheading:12093797-Peroxisome Proliferators,
pubmed-meshheading:12093797-Promoter Regions, Genetic,
pubmed-meshheading:12093797-Protein Binding,
pubmed-meshheading:12093797-Protein Synthesis Inhibitors,
pubmed-meshheading:12093797-Pyrimidines,
pubmed-meshheading:12093797-RNA, Messenger,
pubmed-meshheading:12093797-RNA Stability,
pubmed-meshheading:12093797-Rats,
pubmed-meshheading:12093797-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:12093797-Recombinant Proteins,
pubmed-meshheading:12093797-Time Factors,
pubmed-meshheading:12093797-Tissue Inhibitor of Metalloproteinase-1,
pubmed-meshheading:12093797-Transcription, Genetic,
pubmed-meshheading:12093797-Transcription Factors,
pubmed-meshheading:12093797-omega-N-Methylarginine
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pubmed:year |
2002
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pubmed:articleTitle |
Inhibition of cytokine-induced matrix metalloproteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is indirect and due to a NO-mediated reduction of mRNA stability.
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pubmed:affiliation |
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main D-60590, Germany. w.eberhardt@em.uni-frankfurt.de
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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